Incidence of Kaposi's sarcoma (KS) - a devastating malignancy closely associated with HIV/AIDS - is still very wide-spread in sub-Saharan African countries such as Zambia, where anti-retroviral therapy (ARV) has only recently become available. Human herpesvirus-8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent associated with KS. Our laboratory is widely recognized for its study of the transmission of HIV and HHV-8 and the establishment of a large mother-infant cohort in Zambia to study those two viruses. We were the first to establish that HHV-8 can be transmitted perinatally and together with HIV contribute to the increase of Kaposi's sarcoma in children in Africa. More recently, in collaboration with CDC- GAP Zambia, we determined the early childhood infection rate of HHV-8. As such, we are ideally positioned to lead the proposed study, the first of its magnitude in the African setting. We have found perinatal transmission can occur in utero, but most HHV-8 infections occur during early childhood via horizontal transmission, with HHV-8 seroconversion occurring even in instances where the child's mother or entire household is HHV-8 negative. Moreover, HIV-1 is a major risk factor for HHV-8 infection, and we found HIV-1 infected children have a five-fold higher risk for infection by HHV-8 as compared to uninfected children, most likely due to immune suppression as a result of HIV-1 infection. It is possible that restoration of the immune response via ARV will reduce HHV-8 infection of HIV-1 positive children and enhance the immune response against HHV-8 in infected individuals. Unfortunately, the impact of ARV on HHV-8 transmission and on HHV-8 disease pathogenesis is unknown. We hypothesize that the treatment of HIV-1 infected children by ARV will substantially lower their risk of being infected by HHV-8 and reduce the risk of disease progression toward developing KS in infected children by enhancing their anti-HHV-8 immune response and reducing viral reactivation. The overall objective of the proposed study is to make use of our established study infrastructure to determine the impact of ARV treatment on HHV-8 transmission, on anti-HHV-8 immune response, and on viral reactivation. We propose to utilize relevant participants in our existing cohort and to recruit additional subjects for our proposed study, as appropriate. To test the validity of our hypothesis, we are proposing two aims. The first is to determine whether ARV treatment of HIV-1 infected children will reduce their susceptibility to HHV-8 infection. The second is to determine whether ARV treatment of HIV-1 and HHV-8 dually infected children will enhance their immune response against HHV-8 and reduce viral reactivation. We anticipate that the data generated through the proposed effort will be useful in the development of future intervention strategies to prevent HHV-8 transmission. PUBLIC HEALTH RELEVANCE: For the past 10 years we have studied the mother to child transmission of human herpesvirus-8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus (KSHV), which is associated with Kaposi's sarcoma (KS), a devastating malignancy in AIDS patients in sub-Saharan Africa. With the recent introduction of anti-retroviral therapy (ARV) in Zambia, it is both timely and important to investigate the effects of ARV on HHV-8 infection. Our study will lead to a better understanding of the relative effects of ARV treatment on HHV-8 replication, and it may also lead to more effective KS treatment and prevention guidelines in HIV-infected children.